Overexpression of Lymphocyte Activation Gene-3 Inhibits Regulatory T Cell Responses in Osteoarthritis

Lymphocyte activation gene-3 (LAG-3) is a CD4 homologue expressed on the surface of activated conventional T cells and regulatory T (Treg) cells. In conventional T cells, LAG-3 acts as an inhibitory receptor of T cell inflammation. However, the role of LAG-3 in Treg cells remains controversial. In this study, we investigated the effect of LAG-3 on Tregs in osteoarthritis (OA). We observed that the proportion of LAG-3-expressing cells in CD4⁺CD25^+/high T cells and Foxp3⁺CD4⁺CD25^+/high T cells were significantly upregulated in OA patients. The level of LAG-3-to-Foxp3 ratio was further increased in synovial fluid. Several aspects of Treg responses in LAG-3⁺ and LAG-3^- Treg cells were then examined. First, LAG-3⁺ Treg cells demonstrated significantly lower proliferation than LAG-3^- Treg cells. Second, the increase in interleukin (IL)-10 and transforming growth factor (TGF)-β expression was significantly lower in LAG-3⁺ Treg cells than that in LAG-3^- Treg cells. Third, LAG-3⁺ Treg cells were less capable of inhibiting the proliferation of CD4⁺CD25^- conventional T cells than LAG-3^- Treg cells. This study suggests that Treg cells in OA may be enriched with a LAG-3-expressing population that exhibits functional impairment, which limits their capacity in suppressing inflammation.